Saturday, July 7, 2018

Even if it is medically indicated, there's more and more evidence that using beta-2-agonists (esp. but not exclusively orally) could provide an unfair advantage to athletes: increased protein synthesis, increased mitochondrial neogenesis, established ergogenic effects,...

If you've been following the news, you will be aware that the Tour de France Champion, Chris Froome, has been busted with elevated levels of the beta-2-agonists Salbutamol in his blood (learn more). Now, we could debate forever about whether the green light Froome just got is a case of double-standards or not, but that's not the purpose of this article, anyway. Rather, I want to explain why the claim that salbutamol, officially an asthma medication, wouldn't be a worthwhile doping agent is bullshit.

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I've addressed the (ab-)use and positive side effects of beta-2-agonists in previous articles. Next to proven ergogenic effects in cycling (see "Albuterol / Salbutamol Doping Works!" | read it) these agents have also been shown to have a direct beneficial (=lowering) effect on the protein synthesis brake myostatin (read more). In today's follow-up I want to address a related study, a study in trained men and a study that adds another item to the list of benefits of "having asthma" (and being prescribed clenbuterol, albuterol, salbutamol, etc.) as a cyclist.

Figure 1: From increased protein synthesis to boosted mitochondrial biogenesis the (ab-)use of regular amounts of beta-2-agonists has been shown to have various benefits that would warrant their ban in drug-controlled sports.

In said study, researchers from the Department of Nutrition, Exercise and Sports at the University of Copenhagen (Hostrup 2018) investigated the effect of beta2‐adrenoceptor stimulation on skeletal muscle protein turnover and intracellular signalling - a previously "[, in humans, ] insufficiently explored, particularly in association with exercise" (Hostrup 2018).

The study was a randomized placebo‐controlled crossover study with 12 trained men, in which the Danish researchers probed the effect of beta2‐agonist (6 × 4 mg oral salbutamol) on protein turnover rates, intracellular signalling, and mRNA response in skeletal muscle was investigated 0.5–5 h after quadriceps resistance exercise. In order to standardize the treatment and generate reliable results, ...

"[...e]ach trial was preceded by a four‐day lead‐in treatment period. Leg protein turnover rates were assessed by infusion of [13C6]‐phenylalanine and sampling of arterial and venous blood as well as vastus lateralis muscle biopsies 0.5 and 5 h after exercise.

So, there's no reason to doubt the practically relevant 20% increase in myofibrillar FSR for salbutamol compared to placebo [0.079(±0.007) vs. 0.066(±0.004)% × h−1](P < 0.05) - with both, the relative increase and the net leg phenylalanine balance 0.5–5 h after exercise, i.e. 3.6(±2.6) nmol × min−1 × 100 g, being highly relevant for an athlete, especially in view of the previous observation that benefits are additive and significant gains over time can be expected for at least a few weeks before an already less likely (vs. clenbuterol) beta-2-receptor downregulation occurs.

Figure 2: Hostrup et al. found a practically relevant, statistically significant increase in protein synthesis not just in response to the administration of 6x4mg of salbutamol, but also a baseline effect in response to the 4-day preload at only 4x4mg of the asthma medication - a dosage that is used quite certainly year-round by athletes around the world (Hostrup 2018).

In contrast to what the actually relevant outcome, the increase in protein synthesis, would suggest, the scientists did not observe a relevant decline in myostatin. In fact, the protein that acts as a protein synthesis brake and is meant to limit the domain sizes in skeletal muscle to maintain full functionality increased significantly both 0.5 and 5h after the intervention (see Figure 3):

Figure 3: The changes in regulatory gene expression do not necessarily predict an increase in protein synthesis, but the increase in PGC-1alpha, for example, will also come handy for any endurance athlete (and everyone trying to build a more potent metabolic engine by increasing mitochondrial adaptation to exercise | data from Hostrup 2018).

Even though this adds a question mark after the previously voiced hypothesis that a decrease in myostatin (which has btw. only been observed with clenbuterol, the much longer acting cousin of salbutamol | more), it does not negate that as little as 24mg of salbutamol (in the four days before each trial, the subjects consumed only 16mg/d) and hence less than the recommended maximal daily dose (=8x4 mg per day | drugs.com) for the treatment of asthma triggered a(n over time) performance-relevant increase in protein synthesis in all but two outliers (see Figure 2).

Yes, inhaled beta-2-agonists are less ergogenic than oral drugs, but the same research group has previously demonstrated successfully that the "[d]aily inhalation of terbutaline in near‐therapeutic doses induces skeletal muscle growth" (Jessen 2018 | learn more).

It is thus hardly useful to keep citing Kindermann's 2007 opinion piece stating that ergogenic effects are unlikely to occur, whenever another athlete is busted with elevated levels of beta-2-agonist. The latter is particularly true in view of the fact that Kindermann focussed on inhaled beta-2-agonists, which shouldn't even show up on a blood test as the post-administration serum concentrations tend to be significantly lower than what you'd see after the administration of salbutamol and co in pill form (oral tablet, as it was used in the study at hand).

The poor endurance athletes are most likely to suffer from asthma. Incidentally, those who are treated are also significantly more likely to be among the Olympic medalists... crazy coincidence, right (data from Fitch 2008)?

Data on exactly how many "poor" athletes suffer dearly from asthma and how many of them take the convenient pills 4-8x a day is unfortunately not available. What we do know from the few studies that investigated the (ab-)use of asthma medications showed a prevalence of 16.7% for Olympic athletes (Weiler 1998) - and, among those, no one was as likely to suffer as the group of cyclists (see Figure 4, left)... those poor dudes ;-)

Let's not be unfair, but let's be realistic: In view of the fact that scientists have long speculated that the constant exposure to particulate matter from exhaustive fumes, etc. has long been suspected to contribute to the increased asthma rates in cyclists, it would be unfair to place cyclists with pharmacologically treated asthma under general suspicion. The way officials and now the sports tribunal sweep their abuse under the carper, on the other hand, is clearly unwarranted - the evidence for practically (not just statistically) significant effects on exercise performance and training adaptation (VO2, muscle mass, etc) is there.

And, said research is accumulating quickly and in a way that darkens the shadow the abuse of beta-2-agonists by athletes has been casting for years on the extraordinarily high prevalence of asthma, especially, but not exclusively among elite athletes in endurance sports | Comment!

Weiler, John M., Teresa Layton, and Margaret Hunt. "Asthma in United States Olympic athletes who participated in the 1996 Summer Games." Journal of Allergy and Clinical Immunology 102.5 (1998): 722-726.

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